We previously developed a Drosophila model of mammalian neurodegenerative disease by inactivating the protein kinase Cdk5/p35. This is the fly homolog of one of the main proteins responsible for phosphorylating tau into the form found in the neurofibrillary tangles that are characteristic of many forms of human neurodegeneration. In a paper published this year, we showed that Cdk5 also regulates a developmentally-programmed form of axonal and dendritic disassembly in the fly. Programmed remodeling of the mushroom bodies in the Drosophila central brain bears many mechanistic similarities to the neurite loss seen in disease. We find that Cdk5 controls the timing and rate of axonal and dendritic disassembly, and that it does so in part by controlling the stability of the microtubule cytoskeleton. We also find, however, that Cdk5 must use at least one other mechanism, acting in parallel to its effects on microtubules, which more directly targets the final fragmentation of axons and dendrites late in the neurite disassembly cascade. These data begin to give us a way to discriminate the different Cdk5-dependent mechanisms that contribute to overall neurite disassembly in development and disease. In parallel with these targeted developmental and phenotypic studies of Cdk5/p35, we have also been performing a more broadly-focused systems analysis of the kinase. Here, we have investigated the effects of both loss- and gain-of-function, since we have recently shown that in the fly, as in humans and mice, either gain or loss of Cdk5 induces neuronal death. Remarkably, we found that increase or decrease of Cdk5 activity produces genome-wide changes in gene expression that mimic the effects of aging, and this occurs prior to the onset of any detectable pathology. We therefore used a combination of genome-wide expression profiling and machine learning statistical methods to develop a novel metric for physiological aging, using the internal transcriptomic state of the animal as a measure of its effective age rather than simple clock-time since birth. This metric shows conclusively that modest gain of function of Cdk5 kinase significantly accelerates the intrinsic rate of aging of the adult fly. This is extremely significant, since many, if not most, of the cellular phenotypes that we associate with degeneration are also normal consequences of natural aging. This raises the possibility that defects such as altered autophagy, stress sensitivity and mitochondrial function, rather than being causes of degeneration, are actually second-order consequences of the associated acceleration of aging, making them far less attractive as potential targets for biomarker development and drug design in neurodegenerative disease.
